Tuesday, 31 March 2020

A
new paper reviews the new draft of EU GMP Annex 1. In doing so the focus is on
those aspects that are different to the 2017 draft, rather than spending much
time comparing the 2020 draft with the current Annex 1 (which is dated 2009).

The
review includes an overview of the core changes, which include:

The
global acceptance and implementation of ICH Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System), is
not reflected in the current Annex. The new draft contains many references to
Quality Risk Management (QRM) in particular, emphasizing that QRM should be
used as a proactive tool. There are now 92 instances of the word “risk” in the
new draft, an increase from 20 in the previous version.

There
have been advances in sterile manufacturing technology, especially with RABS
and isolators. There have also been advances with rapid microbiological
methods, which the draft Annex acknowledges.

There
was some ambiguity with the current version and these needed correction or
clarification.

Annex
1 is often beyond sterile manufacturing, including aspects of non-sterile
manufacturing. The scope of the new draft has been modified to reflect this.

There
is the requirement for a formal, holistic contamination control strategy (which
is now abbreviated to ‘CCS’ in the new draft). The expectation now appears to
be for a formal document which reflects the site-wide strategy for minimizing
contamination control with respect to sterile manufacturing .

The
requirements of the contamination control strategy have been widened (43
mentions, up from 19 in the 2017 draft), however, with the new draft, extending
to the need to fully-understand and review design, procedural, technical and
organizational controls.

Monday, 30 March 2020

An isolator is an
arrangement of
physical barriers
that are integrated
so that the
workspace (an
enclosed
environment) within
the isolator is
sealed from the
outside
environment. Isolators provide a testing environment free from contamination,
through routine sanitization using a validated cycle and
confirmed by environmental monitoring.
In addition, these devices enable the isolation between the operator and the process. There are many complications with isolators, from design to qualification, and with general operation.

It certainly remains that isolators cannot prevent contamination
caused by GMP deficiencies such as poor aseptic
procedures and inadequate training of operators.

To address these concerns and to outline best practices, Tim Sandle has written a new Pharmig guide:

Sunday, 29 March 2020

EDQM has posted new guidance on the qualification of gas chromatography equipment.

The document is the second Annex of the core document “Qualification of Equipment”,
and it should be used in combination with it when planning, performing and documenting the GC
equipment qualification process.

The core document contains the general introduction and the Level I and II of qualification,
common to all type of instruments, and the present annex contains GC instrument-related
recommendations on parameters to be checked and the corresponding typical acceptance limits,
as well as practical examples on the methodology that can be used to carry out these checks.

Level III (Periodic and motivated instrument calibration/checks) and IV (In-use instrument checks)
qualifications must be carried out as an ISO 17025 requirement.

The tests proposed in the Level
III and IV of qualification are based on an overall approach, in which several parameters are
checked at the same time in a combined test procedure, to obtain information on the overall
system performance (e.g. peak area precision, retention time precision, temperature programme
reproducibility, etc).
Nevertheless, it should be noted that it is also acceptable to check these parameters individually by
using other well-defined procedures.

Requirements and (if applicable) corresponding typical acceptance limits (given in bold) should be
applied; however other appropriately justified approaches are acceptable. Exemplary procedures
provided in this document have non-binding character. They can be helpful when carrying out the
required qualification.

Nevertheless, it is left to the professional judgement and background
experience of each OMCL to decide on the most relevant procedures to be undertaken in order to
provide evidence that their GC systems are working properly and are suitable for their intended
use. If the qualification of equipment is done by the manufacturer or an external service provider,
it is the responsibility of the OMCL to make sure that this is in line with the requirements set out in
this guideline.

Saturday, 28 March 2020

At its 165th session in November 2019, the European Pharmacopoeia Commission adopted two general chapters related to testing for particulate contamination in pharmaceutical preparations.

The revisions to general chapter 2.9.19. Particulate contamination: sub-visible particles supplement the Pharmacopoeial Discussion Group (PDG) harmonised text with alternative local requirements applicable to biological parenteral preparations. Such preparations are provided in low volumes and the local requirements – marked in the text with white diamonds – allow testing of these and other preparations to be performed using volumes smaller than 5 mL where suitable instrumentation is available. The PDG remains committed to further revising the chapter in order to integrate these changes into the harmonised text.
The new, non-mandatory general chapter 5.17.2. Recommendations on testing of particulate contamination: visible particles provides information on visual inspection and control of visible particles in liquid preparations for which testing according to the general chapter 2.9.20. Particulate contamination: visible particles applies. The text highlights the different sources of foreign particle contamination of liquid preparations and the fact that every effort should be made to avoid their presence. Consideration is given to the different inspection stages during production and quality control, including stability testing. Acceptable quality level (AQL) testing (with reference to ISO standard 2859-1) following a 100% inspection of the batch is also addressed. This chapter is not intended to elaborate on GMP requirements, but rather should be read in conjunction with them. Detection of visible particles in parenteral products is probabilistic in nature and the occurrence of particles is random. The chapter therefore provides guidance on how users can establish that their product is “practically free from particles”.

These two chapters will be published in European Pharmacopoeia (Ph. Eur.) Supplement 10.3 and will become effective on 1 January 2021.

Genomics Investigation of Human Gut Microbiome to Determine Effects of Microgravity Exposures (Rhodium Space Microbiome) examines the effects of spaceflight on the human gut microbiome, a complex community of numerous bacterial species. Developing a better understanding shifts in microbiome diversity and function and how they affect human health and performance may help protect people on future missions. Recent studies have shown a connection between alterations in the structure and function of the gut microbiome and multiple chronic and acute diseases.
Upon return, both sets of samples will be sequenced and analyzed to identify genetic changes that might occur to the bacterial communities, and to understand the potential implications these changes may have to human health in microgravity.

Thursday, 26 March 2020

In many ways, the hemp plant is intertwined with the history of the United States. British settlers even brought a store of hemp seeds along during their journey across the Atlantic and were “compelled by law to grow hemp.” Today, we understand that hemp has numerous medical benefits, but during colonial times, hemp was primarily used in textile and fiber-based applications, at least until 1937.

A guest post by Indiana Lee
That year, Congress passed the Marihuana Tax Act, which effectively made hemp cultivation a crime. At the time, hemp was considered dangerous, lumped in with its cousin marijuana, which has psychoactive effects when ingested or smoked. Yet the hemp plant contains only trace amounts of tetrahydrocannabinol (THC), the cannabinoid that’s responsible for a marijuana user’s “high.”

While, as the most notorious of the estimated 113 cannabinoids found in the cannabis plant, THC gets the bulk of press surrounding the plant, it’s not necessarily the star of the show. For instance, cannabidiol, commonly known as CBD, doesn’t induce euphoria but has shown promise in treating a wide variety of health conditions, from anxiety and insomnia to Alzheimer’s and neurodegenerative disorders.

For this reason, and thanks to the 2018 passage of the Hemp Farming Act of 2018 (H.R.5485), which re-legalized hemp cultivation at the federal level, CBD shops are popping up in strip malls and co-ops across the country. We still have more to learn about CBD, however, and consumers should note that not all products containing CBD are consistently effective.

Like its cousin marijuana, the cellular makeup of hemp can vary considerably between strains, resulting in differing effects depending on an individual's condition and the plant’s potency. In effect, the idea of “CBD” has been oversimplified for the masses, but it’s much more complex than meets the eye.

Cannabis Legalization and Terminology

Fast forward to the 21st century, where, after decades of prohibition, the hemp industry is once again booming. The passage of H.R. 5485 paved the way towards a greater understanding of and research on the ways in which hemp affects the body. (It’s important to note that hemp cultivation is still banned in Idaho and South Dakota.) To be considered “hemp,” a cannabis plant can contain no more than 0.3% THC.

When it comes to medical marijuana, CBD takes center stage as the plant’s most helpful cannabinoid. Derived directly from hemp, CBD interacts with your body’s endocannabinoid system (ECS). According to a 2017 study published on ScienceDirect, the ECS is “involved in many physiological regulation pathways in the human body,” such as mood, memory, appetite, and pain sensations.

ECS receptors and neurotransmitters are lipid-based, which is why CBD extract is often housed in some type of oil for greater effectiveness. The two primary ECS receptors are CB1 and CB2, and THC easily binds to both receptors. CBD, on the other hand, interacts with the ECS in a slightly different manner: The cannabinoid acts as a sort of influencer, modifying a receptor’s ability to bind to other cannabinoids.

Yet cannabinoids don’t work alone when it comes to effects on the body. The hemp plant contains a number of other components that may help determine treatment efficacy, such as terpenes. Like cannabinoids, terpenes are developed in the trichomes of the hemp plant, and are primarily responsible for producing the unique scent of a particular strain. Terpenes also play a role in a plant’s medicinal effects. For example, the limonene terpene (also found in lemons) may improve mood and reduce anxiety.

Efficacy and Medical Uses for CBD

Reducing anxiety, in fact, is one of the most lauded effects of CBD. Studies indicate that CBD may directly activate the 5-HT1A serotonin receptor, inducing anti-anxiety and antidepressant effects. Therefore, CBD could ultimately replace a number of pharmaceutical medications, many of which come with negative side effects and may be addictive.

For its part, CBD is considered non-addictive and may also help with pain relief. To wit, researchers have proposed the use of CBD as an alternative to opioids for managing chronic pain. Opioid misuse has become a scourge on society in recent years, and preliminary data indicates that “opioid overdoses and abuse have been significantly lower in states that have legalized cannabinoids,” writes the Psychiatric Times. However, that data is in dispute, and more research is needed.

For now, we can at least focus on the proven benefits of CBD, including the reduction of seizure frequency on some patients. According to the American Epilepsy Society, CBD has been shown to reduce seizures among patients with treatment-resistant epilepsy, but CBD treatment effectiveness may wane over time, requiring higher doses. CBD works against seizures by conferring neuroprotective effects to the hippocampus, and side effects of the treatment may include nausea and vomiting.

How CBD is Becoming a Mainstream Treatment Option

But the benefits of CBD may not be accessible to everyone. Despite the ubiquity of CBD and hemp shops across the U.S., many patients still lack access to the versatile cannabinoid. Although hemp is federally legal, many state legislators still have difficulty differentiating between its components, continuing to lump THC and CBD into the same category of dangerous substances, nearly 100 years after the implementation of the Marihuana Tax Act.

On a public health scale, the legal status of CBD is problematic. Ensuring high-quality care across diverse populations hinges on the concept of ranges — ranges of populations, conditions, choices, where both providers and patients can work together with a variety of options to create personalized treatment plans. Especially for those patients who have tried other methods without success, access to CBD may be paramount to long-term healing.

We still have a long way to go before the entire nation has access to alternative treatments like CBD and its potential benefits. Despite legal roadblocks, plenty of research on cannabidiol is being conducted, including the creation of enzymatic networks in yeast strains. As such, CBD promises to be an exciting component of the medical landscape well into the future.

Wednesday, 25 March 2020

The
ability of pathogens to multiply in the host is crucial for the spread of
infections. The speed of bacterial division greatly depends on the
environmental conditions. Under unfavorable conditions, such as nutrient
deficiency, bacteria tend to pause after division and reproduce more slowly.
But how do bacteria know, when it is time to enter the next round of cell
division?

A
team at the Biozentrum of the University of Basel, led by Prof. Urs Jenal has
now identified a central switch for reproduction in the model bacterium
Caulobacter crescentus: the signaling molecule c-di-GMP.

Under
favorable living conditions, newborn bacteria begin to produce the signaling
molecule -- this starts the clock ticking. The initially low c-di-GMP level
activates a first kinase. This activates the expression of over 100 genes,
which drive the cell towards division and boost the production of c-di-GMP.

The
resulting peak levels of c-di-GMP finally stimulate the last wheel of the
machinery, also a kinase.

Monday, 23 March 2020

LAL
testing is an established part of many QC microbiology laboratories, and
subject to the similar test protocols and assay requirements as with other
analytical methods, albeit with the wider acceptance criterion that reflects
the test’s status as a biological assay. With such laboratory methods there
will be times when a laboratory will either need to transfer an existing method
between one laboratory an another or where the core reagent needs to be
changed; both scenarios require a reassessment of previously assessed samples.
This article, in considering analytical method changes, uses the LAL test
(specifically a photometric test method) as an example of how a method can be
transferred.

In
relation to this, Tim Sandle and Kerry Skinner have written an article. Here is
the abstract:

A
key objective is with any method transfer or change is ensuring that product
and process knowledge is captured. Challenges with this process can arise
because of poor analytical method robustness; where differences in analytical
technology that have not been duly considered; due to different working
cultures; or where there are differences in ways of working between
laboratories or alterations that are required in relation to different
methodologies. Such issues are more likely when a method is transferred but
problems can also arise when a reagent changes, especially where the
replacement reagent is inferior. The important aspect will both scenarios is in
taking time to plan the change process.

Sunday, 22 March 2020

An antioxidant found in green tea plant could help in fighting tuberculosis. The compound is epigallocatechin gallate and it can inhibit the growth of a tuberculosis-causing bacteria strain. This may pave the way for the development of novel drugs.
The development comes from Nanyang Technological University, Singapore (Singapore), where scientists have demonstrated that the antioxidant called epigallocatechin gallate can inhibit the growth of the Mycobacterium tuberculosis. The researchers have shown that the compound binds to an enzyme (ATP synthase) that provides energy to bacterial cells. When pigallocatechin gallate becomes attached to the enzyme, the available energy for critical processes required for bacterial cell division is reduced, leading to inhibition.

Tuberculosis is one of the most widespread bacterial diseases on the planet. It is an infection that has plagued humans for over millennia. Symptoms of infection from this bacterial disease include a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss.

In terms of the significance of the research, if it can be determined areas on the enzyme where the compound binds and dampens energy production, then it could be possible to develop a drug product to help fight the bacteria and prevent the course of an infection in a patient.

Speaking with Laboratory Roots, lead researcher Professor Gerhard Grüber says: "Though tuberculosis is curable, the success of current drugs on the market is increasingly being overshadowed by the bacteria's clinical resistance. Our discovery of the EGCG's ability to inhibit the growth of M. tuberculosis will allow us to look at how we can improve the potency of this compound in green tea, and other similar compounds, to develop new drugs to tackle this airborne disease."

The research has been published in the journal Scientific Reports. The research paper is titled "Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis."

Saturday, 21 March 2020

Bacterial vaginosis (BV) is the most common vaginal disorder worldwide in women of the reproductive age and is associated with the increased risk of upper reproductive tract infections, adverse pregnancy outcomes, and high susceptibility to sexually transmitted infections.

Currently antibiotics are the mainstay of therapy for BV, however, the recurrence rate is up to 70 % within a year. BV is characterized by a microbial imbalance of the vaginal flora, predominantly the loss of normally dominant Lacobacilli and the overgrowth of anaerobic bacteria. More than a dozen bacterial species have been identified to be associated with BV, among them species of the genus Gardnerella were found to be the most prevalent, and without them BV symptoms seem not to occur.

PhagoMed isolated a panel of bacteriophage endolysins, highly evolved hydrolytic enzymes, that specifically degrade the bacterial cell wall of all tested species within the genus Gardnerella. By genetic engineering the lytic activity of these endolysins was further enhanced whereat the specificity for Gardnerella spp. was still preserved.

When testing these endolysins on different Lactobacilli strains their viability was not affected.

This combination of high selectivity as well as high effectiveness in killing Gardnerella makes endolysins a very attractive alternative to antibiotics for the treatment of BV.

Friday, 20 March 2020

New research indicates enhancing human body cells so that they are more attuned to killing invasive Mycobacterium tuberculosis is an effective means for controlling the spread of the disease. The approach involves harnessing RNA sensors, which detect the RNA of invading pathogens. The research is also of wider pathology interest since RNA sensor molecules were previously thought to be involved in fighting viruses and not bacteria; the new study shows their role in combating invasive bacteria.

The new research strand aims to trigger human cells to become effective at killing M. tuberculosis cells by harnessing RNA sensors. The aim is to enhance the detection of invading pathogens and to increase the possibility of the body’s immune system in killing the invaders before they can secrete effector proteins. RNA sensors are part of the innate immune system and they are initiated by recognition of pathogen-associated molecular patterns. Such recognition initiates signalling cascades that culminate in a coordinated intracellular innate immune response designed to control infection.

Thursday, 19 March 2020

Acne is a common skin condition, affecting people at different ages, and one that can wreak havoc with your self-esteem and often appears at the worst possible time. New research identifies some strategies for dealing with the condition.

To help to increase the knowledge around the condition of acne, the website eMediHealth has completed an in-depth survey about the skin condition acne. To arrive at the findings, 64 dermatologists participated in the research (including those based in the U.S., U.K. Canada and Australia). The research output reveals some interesting facts about acne, as well as common mistakes people make while attempting to deal with the condition.

Acne vulgaris refers to a long-term skin disease, which arises when hair follicles become clogged with dead skin cells and oil from the skin. There is also a probable association with the anaerobic bacterium Cutibacterium acnes, in that increased sebum production creates an environment that can sustain the colonization of the bacterium. The condition is often a source of discomfort for people and it is connected with mental health issues, such as low self-esteem.

Why acne occurs

The research produced a number of interesting findings about acne. The first relates to the most common skin type associated with the condition. Here the overwhelming majority (92.1 percent) of the dermatologists connected the condition to oily skin. This is because those with oily skin tend to have overactive oil glands that produce excessive sebum.

As to why certain people have a tendency to develop acne, hormonal imbalance was stated to play a major role in the development of acne and was identified as the top trigger for acne, Other causative factors were identified as high levels of stress and excessive sugar intake.

However, other factors that have been commonly associated with the development of acne, like smoking (20.31 percent), pollution (17.18 percent), and dust (7.81 percent), were rated low by the experts.

In terms of the after-effects of acne, more than half (55 percent) of the participants in the study held the view that the risk of scarring largely depends on the type of acne, and 28 percent believed that it depends on both the type of acne and the medication used to treat it. Generally, inflammatory acne is viewed as more likely to lead to scarring compared with non-inflammatory acne.

Dealing with acne

In terms of strategies for dealing with acne, ensuring that all make-up is thoroughly removed was found to be important. With this issue, 70.31 percent of the dermatologists emphasized the importance of removing every trace of makeup before a person with acne goes to bed. This is necessary so that the skin can breathe easily while the person sleeps.

Another factor to take into consideration for minimizing acne relates to skin cleaning. 78.13 percent cited that excessive skin cleaning, along with scrubbing, represents a common mistake made by patients with acne.

Where acne is severe, the dermatologists stressed the importance of seeking advice. With this issue, 79.69 percent said that too many patients with acne usually make the error of not seeking dermatological help, which can worsen their condition.

With standard acne treatments, isotretinoin and retinoids (medications that are derived from vitamin A) emerged as clear favorites among the dermatologists, each registering 75 percent of the votes.

As a word of warning for those with acne considering self-medicating, the overall effectiveness of home remedies for acne was deemed to be low. This means those looking for quick solutions through unverified treatments or remedies should take care. A total of 46.88 percent of the dermatologists stated that none of the ‘alternative’ remedies are likely to yield any significant results, and only 3.13 percent felt that the listed acne remedies may be helpful in some way.

Of these alternatives, witch hazel topped the list with 17.9 percent of the votes, followed by essential oils, which were recommended by 15.63 percent of the respondents.

For people with mild acne, the advice is to speak to a pharmacist or seek advice from a dermatologist about the appropriate medicines to treat it. For those with severe acne, advice from a medical practitioner should be sought.